Drugs of abuse are a significant co-factor in HIV infection. Although it has been postulated that drugs of abuse may also represent significant co-factors in disease progression, addressing this hypothesis has been problematic. We have obtained preliminary data that such an interaction indeed occurs between the commonly used psychostimulant methamphetamine (METH) and SIV, and propose here to further investigate this interaction. Both METH and SIV/HIV affect the brain, and many of the mechanisms and sites of damage converge for these two agents. We have found increased neurophysiological deficits in animals receiving both agents. Furthermore, signs of simian AIDS appeared within the study period only in SIV-infected animals receiving METH. Furthermore, METH-treated SIV-infected animals developed a kidney disease not seen in the other animals. We propose here to study the interactions of SIV and METH in systemic and organ-specific damage and dysfunction. Our working hypothesis is that at least three distinct areas of interaction occur between these agents that combine to increase disease: a combined toxic effect in the CNS, an interaction in the immune system, and an induction of renal disease. Specifically, in our three aims, we will examine functional measures of physiology and neuronal circuitry, viral load, and histopathological and neurostructural indicators for interactions of METH and SIV in the CNS. Systemic/peripheral (non-CNS) manifestations of disease will also be examined, in terms of viral load, immune function, and renal pathophysiology. In addition to in vivo and pathological studies, we will perform in vitro studies on CCL15, a proinflammatory chemokine found to be upregulated by METH in astrocytes, and a potential mediator of neuronal injury. Through these appropriately powered, controlled experiments, we will determine the nature of the interaction between METH and SIV, and uncover important mechanisms relevant to human health. [unreadable] [unreadable]